The present invention is related to novel nitrogen ring compounds, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are useful in therapy, and in particular for the treatment of pain.
The xcex4 receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Ligands for the xcex4 receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the xcex4 receptor have also been shown to possess immunomodulatory activities.
The identification of at least three different populations of opioid receptors (xcexc, xcex4 and xcexa) is now well established and all three are apparent in both central and peripheral nervous systems of many species including man. Analgesia has been observed in various animal models when one or more of these receptors has been activated.
With few exceptions, currently available selective opioid xcex4 ligands are peptidic in nature and are unsuitable for administration by systemic routes. Some non-peptidic xcex4 antagonists have been available for some time (see Takemori and Portoghese, 1992, Ann. Rev. Pharmacol. Tox., 32: 239-269. for review). These compounds, e.g. naltrindole, suffer from rather poor (i.e.,  less than 10-fold) selectivity for the xcex4 receptor vs. xcexc receptor binding and exhibit no analgesic activity, a fact which underscores the need for the development of highly selective non-peptidic xcex4 ligands.
Thus, the problem underlying the present invention was to find new analgesics having improved analgesic effects, but also with an improved side-effect profile over current xcexc agonists and potential oral efficacy.
Analgesics that have been identified and are existing in the prior art have many disadvantages in that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that preferred compounds, described within the prior art, show significant convulsive effects when administered systemically.
The problem mentioned above has been solved by developing novel compounds which possess a piperidine ring, which may be a 5-membered, a 6-membered or a 7-membered nitrogen ring, as will be described below.
The novel compounds according to the present invention are defined by the general formula (I) 
wherein
m is 0 or 1;
n is 1 or 2;
R1 is selected from
hydrogen;
a branched or straight C1-C6 alkyl;
C3-C8 cycloalkyl;
C4-C8(alkyl-cycloalkyl) wherein alkyl is C1-C2 alkyl and cycloalkyl is C3-C6 cycloalkyl; benzyl; 
xe2x80x83where G is a hydroaromatic or a heteroaromatic group having 5 or 6 atoms, and where the heteroatoms are selected from O, S and N; and 
and wherein n=0 or 1;
C6-C10 aryl; or heteroaryl having from 5 to 10 atoms selected from any of C, S, N and O;
wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents independently selected from any of hydrogen, CH3, (CH2)pCF3, halogen, CONR5R4, COOR5, COR5, (CH2)pNR5R4, (CH2)pCH3(CH2)pSOR5R4, (CH2)pSO2R5, and (CH2)pSO2NR5, wherein R4 and R5 is each and independently as defined for R1 above and p is 0, 1 or 2;
(C1-C2 alkyl)-(C6-C10 aryl); or (C1-C2 alkyl)heteroaryl, the heteroaryl moieties having from 5 to 10 atoms selected from any of C, S, N and O, and where the aryl or heteroaryl may optionally and independently be substituted by 1 or 2 substituents independently selected from any of hydrogen, CH3, CONR5R4, COOR5, COR5, (CH2)qNR5R4, (CH2)qCH3(CH2)qSOR5R4, (CH2)qSO2R5, (CH2)qSO2NR5, and (CH2)qOR4, wherein R4 and R5 is each and independently as defined for R1 above and q is 0, 1 or 2;
A is 
xe2x80x83wherein R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18 is each and independently as defined for R1 above and wherein the phenyl ring of each A substituent may be optionally and independently substituted by 1 or 2 substituents Z1 and Z2 which are each and independently selected from hydrogen, CH3, (CH2)rCF3, halogen, CONR2R3, CO2R2, COR2, (CH2)rNR2R3, (CH2)rCH3(CH2)rSOR2, (CH2)rSO2R2 and (CH2)rSO2NR2R3 wherein R2 and R3 is each and independently as defined for R1 above and wherein r is 0, 1 or 2; X is O S or NR19 where R19 is as defined for R1.
B is a substituted or unsubstituted aromatic, heteroaromatic, hydroaromatic or heterohydroaromatic moiety having from 5 to 10 atoms selected from any of C, S, N and O, optionally and independently substituted by 1 or 2 substituents independently selected from hydrogen, CH3, (CH2)tCF3, halogen, (CH2)tCONR5R4, (CH2)tNR5R4, (CH2)tCOR5, (CH2)tCOOR5, OR5, (CH2)tSOR5, (CH2)tSO2R5, and (CH2)tSO2NR5R4, wherein R4 and R5 is each and independently as defined for R1 above, and t is 0, 1, 2 or 3;
Within the scope of the invention are also pharmaceutically acceptable salts of the compounds of the formula (I), as well as isomers, hydrates, isoforms and prodrugs thereof.
Preferred compounds according to the invention are compounds of the formula (I) wherein
R1 is selected from benzyl; 
xe2x80x83where G is a hydroaromatic or a heteroaromatic group having 5 or 6 atoms, and where the heteroatoms are selected from O, S and N; and 
xe2x80x83and wherein n=0 or 1;
A is selected from anyone of 
xe2x80x83wherein R6, R7, R8, R9, R16, R17 and R18 is each and independently as defined for R1 above; and Z1, Z2 and X is each and independently as defined above;
B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, and indazolinyl, each optionally and independently substituted by 1 or 2 substituents independently is selected from hydrogen, CH3, CF3, halogen, xe2x80x94(CH2)tCONR5R4, xe2x80x94(CH2)tNR5R4, xe2x80x94(CH2)tCOR5, xe2x80x94(CH2)tCO2R5, and xe2x80x94OR5,
wherein t is 0 or 1, and wherein R4 and R5 are as defined above.
Especially preferred compounds are compounds of the formula (I) wherein
R1 is (C1-C2 alkyl)phenyl and hydrogen;
A is 
xe2x80x83wherein R6, R7, R8, R 9 is each an ethylene group; and Z1 and Z2, are as defined above;
B is phenyl or naphtalene; and
m and n is each 1, or m is 1 and n is 0.
The substituents A and B respectively, may optionally be substituted at any position of the ring.
By xe2x80x9chalogenxe2x80x9d we mean chloro, fluoro, bromo and iodo.
By xe2x80x9carylxe2x80x9d we mean an aromatic ring having from 6 to 10 carbon atoms, such as phenyl and naphtyl.
By xe2x80x9cheteroarylxe2x80x9d we mean an aromatic ring in which one or more of the from 5-10 atoms in the ring are elements other than carbon, such as N, S and 0.
By xe2x80x9chydroaromaticxe2x80x9d we mean a partly or fully saturated aromatic ring structure having from 5-10 carbon atoms in the ring.
By xe2x80x9cheterohydroaromaticxe2x80x9d we mean a partly or fully saturated aromatic ring structure in which one or more of the from 5-10 atoms in the ring are elements other than carbon, such as N, S and 0.
By xe2x80x9cisomersxe2x80x9d we mean compounds of the formula (I), which differ by the position of their functional group and/or orientation. By xe2x80x9corientationxe2x80x9d we mean stereoisomers, diastereoisomers, regioisomers and enantiomers.
By xe2x80x9cisoformsxe2x80x9d we mean compounds of the formula (I) which differ by their crystal lattice, to such as crystalline compound and amorphous compounds.
By xe2x80x9cprodrugxe2x80x9d we mean pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product of the derivative is the active drug. The reference by Goodman and Gilmans, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, xe2x80x9cBiotransformation of Drugs, p. 13-15, describing prodrugs generally, is hereby incorporated.
The novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chromic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive.
Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti tumour agents and anti viral agents.
Compounds of the invention are useful in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
Compounds of the invention are useful for the treatment of diarrhoea, depression, urinary incontinence, various mental illnesses, cough, lung oedema, various gastrointestinal disorders, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (eg. Amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotica, anxiolytics, neuromuscular blockers and opioids.
The compounds of the present invention in isotopically labelled form are useful as a diagnostic agent.
Also within the scope of the invention is the use of any of the compounds according to the formula (I) above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.
A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula (I) above, is administered to a patient in need of such treatment.
Methods of Preparation
Compounds of the formula (I), as described above, may be obtained by the arylation of an amine of formula (II) 
wherein R1, m and n are as defined in formula (I) above, and W is A or B as defined in formula (I) above, by an arylating agent of formula (III)
Wxe2x80x94Zxe2x80x83xe2x80x83(III)
wherein W is A or B as defined in formula (I) above, and Z is a suitable substituent, i.e. a reactive component suitable to be used in the defined process, which will be appreciated by a person skilled in the art, preferably halogen, triflate (CF3SO3xe2x80x94), mesylate (CH3SO3xe2x80x94), tosylate (CH3(C6H4)SO3xe2x80x94), tributyltin, triacetoxylead, diarylbismuth, borate (B(OH)2), cuprate or other such group known in the art. The arylation may be catalyzed by metals, preferably Cu, Ni, Pd or suitable salts, complexes, oxides or hydroxides thereof. The 4-aminopiperidine of formula (II) above may be converted completely or partially to its corresponding anion by treatment with bases, preferably triethylamine, 4-dimethyl-aminopyridine, K2CO3, NaOH, NaH, lithium diisopropylarnide, sodium tert-butoxide or the like, prior or during the arylation process. The reaction may be performed in the presence of complexing reagents, preferably triphenylphosphine, triphenylarsine, dibenzyl-ideneacetone, 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphtyl, 1,1xe2x80x2-bis(diphenylphosphino)-ferrocene, oxygen or other such compounds known in the art. The reaction may optionally be performed in the presence of one or more solvents such as toluene, dichloromethane, tetrahydrofuran, dimethylformamide, dioxane, acetonitrile or dimethylsulfoxide, or in solvent mixtures.
R1 and the substituents on A and B of compound (I) as defined above, may be modified after or during the preparation of (I) from (II) and (III) by methods known in the art, for example reduction, oxidation and alkylation.
The amine of formula (II) may be prepared by reductive amination of a ketone of the formula (IV) 
wherein R1, R2, R3, m and n are as defined in formula (I) above, with a substituted arylamine (V)
Wxe2x80x94NH2xe2x80x83xe2x80x83(V)
wherein W is as defined in formula (II) above.
The reductive amination may be performed in a one or a two stage process involving a Brxc3x8nstedt or a Lewis acid and a reducing agent. Suitable acids are sulphuric acid, polyphosphoric acid, 4-toluenesulphonic acid, titanium iso-propoxide, aluminium trichloride, boron trifluoride diethyl etherate, or the like. Suitable reducing agents are hydrogen in the presence of a catalyst, preferably Pd, Pdxe2x80x94C, Pd(OH)2, PtO2, Rhxe2x80x94C or Raney-Nickel, sodium borohydride, sodium cyaneborohydride, lithium aluminumhydride, diborane, di-iso-butylaluminiumhydride, or the like. The reaction may be performed in the presence of one or more solvents which may be organic or inorganic, such as toluene, dichloromethane, ethers, alcohols, acetic acid, water, or in solvent mixtures.
R1 and the substituents on W of compound (II), as defined above, may be modified after or during preparation of (I) from (II) and (m), by methods known in the art, for example reduction, oxidation and alkylation, after or during the preparation of (II) from (IV) and (V).
Compounds of formula (III), (IV) and (V) may be commercially available, prepared by literature procedures or prepared by methods known in the art.